Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

Mast cells (MCs) are main effector cells in allergic inflammation and after activation, they release stored (histamine, heparin, proteases) and newly synthesized (lipid mediators and cytokines) substances. In the gastrointestinal tract the largest MC population is located in the lamina propria and submucosa whereas several signals such as the cytokine IL-4, seem to increase the granule content and to stimulate a remarkable expansion of intestinal MCs. The broad range of MC-derived bioactive molecules may explain their involvement in many different allergic disorders of the gastrointestinal tract. Annexin A1 (AnxA1) is a 37 KDa glucocorticoid induced monomeric protein selectively distributed in certain tissues. Its activity can be reproduced by mimetic peptides of the N-terminal portion, such as Ac2-26, that share the same receptor FPR-L1. Although previous reports demonstrated that AnxA1 inhibits MC degranulation in murine models, the effects of exogenous peptide Ac2-26 on intestinal MCs or the biological functions of the Ac2-26/FPR2 system in human MCs have been poorly studied. To determine the effects of Ac2-26 on the function of MCs toward the possibility of AnxA1-based therapeutics, we treated WT and IL-4 knockout mice with peptide Ac2-26, and we examined the spontaneous and compound 48/80 stimulated colonic MC degranulation and cytokine production. Moreover, in vitro, using human mast cell line HMC-1 we demonstrated that exogenous AnxA1 peptide is capable of interfering with the HMC-1 degranulation in a direct pathway through formyl peptide receptors (FPRs). We envisage that our results can provide therapeutic strategies to reduce the release of MC mediators in inflammatory allergic processes.

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Fluctuation of annexin-A1 positive mast cells in chronic granulomatous inflammation

Inflammation Research ◽

10.1007/s00011-008-7222-7 ◽

2008 ◽

Vol 57 (10) ◽

pp. 450-456 ◽

Cited By ~ 20

Author(s):

S. M. Oliani ◽

G. A. Panin Ciocca ◽

T. A. Pimentel ◽

A. S. Damazo ◽

L. Gibbs ◽

...

Keyword(s):

Mast Cells ◽

Granulomatous Inflammation ◽

Annexin A1

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Heterogeneity of mast cells and expression of Annexin A1 protein in a second degree burn model with silver sulfadiazine treatment

PLoS ONE ◽

10.1371/journal.pone.0173417 ◽

2017 ◽

Vol 12 (3) ◽

pp. e0173417 ◽

Cited By ~ 7

Author(s):

Helena Ribeiro Souza ◽

Lucas Ribeiro de Azevedo ◽

Lucas Possebon ◽

Sara de Souza Costa ◽

Melina Mizusaki Iyomasa-Pilon ◽

...

Keyword(s):

Mast Cells ◽

Silver Sulfadiazine ◽

Annexin A1 ◽

Degree Burn ◽

Second Degree

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Triple-Negative Breast Cancer with High Levels of Annexin A1 Expression Is Associated with Mast Cell Infiltration, Inflammation, and Angiogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms20174197 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4197 ◽

Cited By ~ 24

Author(s):

Maiko Okano ◽

Masanori Oshi ◽

Ali Linsk Butash ◽

Eriko Katsuta ◽

Kazunoshin Tachibana ◽

...

Keyword(s):

Breast Cancer ◽

Mast Cell ◽

Mast Cells ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Immune Cell ◽

High Expression ◽

Cell Infiltration ◽

Annexin A1 ◽

Aggressive Phenotype

Annexin A1 (ANXA1) is a phospholipid-linked protein involved in inflammation, immune response, and mast cell reactivity. Recently, we reported that ANXA1 is associated with aggressive features of triple-negative breast cancer (TNBC); however, its clinical relevance remains controversial. We hypothesized that human TNBC with high expression of ANXA1 mRNA is associated with pro-cancerous immune cell infiltration, including mast cells, and with an aggressive phenotype. Clinical and RNA-seq data were obtained from The Cancer Genome Atlas (TCGA, n = 1079) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n = 1904). TNBC patients had significantly higher levels of ANXA1 expression compared to the other subtypes in both TCGA and METABRIC cohorts (p < 0.001). ANXA1 protein expression was assessed by immunohistochemistry in Japanese TNBC patient cohort (n = 48), where 17 cases (35.4%) had positive ANXA1 staining, and their overall survival was significantly shorter compared with negative staining group (p = 0.008). The CIBERSORT algorithm was used to calculate immune cell infiltrations. ANXA1 high tumors were associated with activated mast cells and M2 macrophages (p > 0.01), but did not show any association with tumor heterogeneity nor cytolytic activity. High expression of ANXA1 group enriched inflammation, epithelial-to-mesenchymal transition (EMT), and angiogenesis-related genes in a gene set enrichment assay in both cohorts. To our knowledge, this is the first study to demonstrate that ANXA1 is associated with infiltration of mast cells and inflammation that is associated with the aggressive phenotype of TNBC, such as EMT and angiogenesis.

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Regulation of Cytosolic Phospholipase A2 Phosphorylation by Proteolytic Cleavage of Annexin A1 in Activated Mast Cells

The Journal of Immunology ◽

10.4049/jimmunol.1102306 ◽

2012 ◽

Vol 188 (11) ◽

pp. 5665-5673 ◽

Cited By ~ 21

Author(s):

Joon Hyun Kwon ◽

Jea Hwang Lee ◽

Ki Soon Kim ◽

Youn Wook Chung ◽

Ick Young Kim

Keyword(s):

Mast Cells ◽

Phospholipase A2 ◽

Proteolytic Cleavage ◽

Cytosolic Phospholipase A2 ◽

Annexin A1 ◽

Cytosolic Phospholipase

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Cytochemical analysis of mast cell granules after poly-dl-lysine action

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010008225x ◽

1978 ◽

Vol 36 (2) ◽

pp. 278-279

Author(s):

R. Courtoy ◽

L.J. Simar ◽

J. Christophe

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Chemical Compounds ◽

Cellular Membrane ◽

Thin Sections ◽

Organic Bases ◽

Ferric Thiocyanate ◽

Cytochemical Analysis ◽

Mast Cell Granule ◽

Amine Liberation

Several chemical compounds induce amine liberation from mast cells but do not necessarily provoque the granule expulsion. For example, poly-dl-lysine induces modifications of the cellular membrane permeability which promotes ion exchange at the level of mast cell granules. Few of them are expulsed but the majority remains in the cytoplasm and appears less dense to the electrons. A cytochemical analysis has been performed to determine the composition of these granules after the polylysine action.We have previously reported that it was possible to demonstrate polyanions on epon thin sections using a cetylpyridinium ferric thiocyanate method. Organic bases are selectively stained with cobalt thiocyanate and the sulfhydryle groups are characterized with a silver methenamine reaction. These techniques permit to reveal the mast cell granule constituents, i.e. heparin, biogenic amines and basic proteins.

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The relationship of IGE receptor topography to signaling activity in RBL-2H3 mast cells

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100085484 ◽

1991 ◽

Vol 49 ◽

pp. 236-237

Author(s):

J.R. Pfeiffer ◽

J.C. Seagrave ◽

C. Wofsy ◽

J.M. Oliver

Keyword(s):

Mast Cells ◽

Protein A ◽

Scattered Electron ◽

Ige Receptor ◽

Receptor Complexes ◽

Ige Binding ◽

Electron Imaging ◽

Small Clusters ◽

Relationship Of ◽

The Relationship

In RBL-2H3 rat leukemic mast cells, crosslinking IgE-receptor complexes with anti-IgE antibody leads to degranulation. Receptor crosslinking also stimulates the redistribution of receptors on the cell surface, a process that can be observed by labeling the anti-IgE with 15 nm protein A-gold particles as described in Stump et al. (1989), followed by back-scattered electron imaging (BEI) in the scanning electron microscope. We report that anti-IgE binding stimulates the redistribution of IgE-receptor complexes at 37“C from a dispersed topography (singlets and doublets; S/D) to distributions dominated sequentially by short chains, small clusters and large aggregates of crosslinked receptors. These patterns can be observed (Figure 1), quantified (Figure 2) and analyzed statistically. Cells incubated with 1 μg/ml anti-IgE, a concentration that stimulates maximum net secretion, redistribute receptors as far as chains and small clusters during a 15 min incubation period. At 3 and 10 μg/ml anti-IgE, net secretion is reduced and the majority of receptors redistribute rapidly into clusters and large aggregates.

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Magnesium and sulfur in mast cell and basophil granules of lower vertebrates in relation with histamine

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100132613 ◽

1992 ◽

Vol 50 (2) ◽

pp. 1596-1597

Author(s):

Kenichi Takaya

Keyword(s):

Electron Microscopy ◽

Transmission Electron Microscopy ◽

Mast Cell ◽

Mast Cells ◽

Tree Frog ◽

X Ray ◽

Transmission Electron ◽

Scanning Transmission ◽

Fresh Frozen ◽

Ultrathin Sections

Mast cell and basophil granules of the vertebrate contain heparin or related sulfated proteoglycans. Histamine is also present in mammalian mast cells and basophils. However, no histamine is detected in mast cell granules of the amphibian or fish, while it is shown in those of reptiles and birds A quantitative x-ray microanalysis of mast cell granules of fresh frozen dried ultrathin sections of the tongue of Wistar rats and tree frogs disclosed high concentrations of sulfur in rat mast cell granules and those of sulfur and magnesium in the tree frog granules. Their concentrations in tree frog mast cell granules were closely correlated (r=0.94).Fresh frozen dried ultrathin sections and fresh air-dried prints of the tree frog tongue and spleen and young red-eared turtle (ca. 6 g) spleen and heart blood were examined by a quantitative energy-dispersive x-ray microanalysis (X-650, Kevex-7000) for the element constituents of the granules of mast cells and basophils. The specimens were observed by transmission electron microscopy (TEM) (80-200 kV) and followed by scanning transmission electron microscopy (STEM) under an analytical electron microscope (X-650) at an acceleration voltage of 40 kV and a specimen current of 0.2 nA. A spot analysis was performed in a STEM mode for 100 s at a specimen current of 2 nA on the mast cell and basophil granules and other areas of the cells. Histamine was examined by the o-phthalaldehyde method.

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The protease phenotype and crystalline nature of the granules of intraepithelial mast cells in Trichinella spiralis-infected mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100140464 ◽

1995 ◽

Vol 53 ◽

pp. 818-819

Author(s):

D.S. Friend ◽

N. Ghildyal ◽

M.F. Gurish ◽

K.F. Austen ◽

R.L. Stevens

Keyword(s):

Small Intestine ◽

Mast Cells ◽

Epithelial Cells ◽

Lamina Propria ◽

Trichinella Spiralis ◽

Intestinal Epithelial ◽

Carboxypeptidase A ◽

C3h Mice ◽

Granule Morphology ◽

Crystalline Nature

Trichinella spiralis induces a profound mastocytosis and eosinophilia in the small intestine of the infected mouse. Mouse mast cells (MC) store in their granules various combinations of at least five chymotryptic chymases [designated mouse MC protease (mMCP) 1 to 5], two tryptic proteases designated mMCP-6 and mMCP-7 and an exopeptidase, carboxypeptidase A (mMC-CPA). Using antipeptide, protease -specific antibodies to these MC granule proteases, immunohistochemistry was done to determine the distribution, number and protease phenotype of the MCs in the small intestine and spleen 10 to >60 days after Trichinella infection of BALB/c and C3H mice. TEM was performed to evaluate the granule morphology of the MCs between intestinal epithelial cells and in the lamina propria (mucosal MCs) and in the submucosa, muscle and serosa of the intestine (submucosal MCs).As noted in the table below, the number of submucosal MCs remained constant throughout the study. In contrast, on day 14, the number of MCs in the mucosa increased ~25 fold. Increased numbers of MCs were observed between epithelial cells in the mucosal crypts, in the lamina propria and to a lesser extent, between epithelial cells of the intestinal villi.

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Mast cell-nerve fiber interaction: Ultrastructural studies

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100159680 ◽

1990 ◽

Vol 48 (3) ◽

pp. 428-429

Author(s):

E.Y. Chi ◽

M.L. Su ◽

Y.T. Tien ◽

W.R. Henderson

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Substance P ◽

Nerve Fiber ◽

Sensory Nerves ◽

Ultrastructural Studies ◽

Morphological Studies ◽

Granulocyte Infiltration ◽

Intracutaneous Injection ◽

Recent Attention

Recent attention has been directed to the interaction of the nerve and immune systems. The neuropeptide substance P, a tachykinnin which is a neurotransmitter in the central and peripheral nervous systems produces tissue swelling, augemntation of intersitial fibrin deposition and leukocyte infiltration after intracutaneous injection. There is a direct correlation reported between the extent of mast cell degranulation at the sites of injection and the tissue swelling or granulocyte infiltration. It has previously been demonstrated that antidromic electrical stimulation of sensory nerves induces degranulation of cutaneous mast cells, cutaneous vasodilation and augmented vascular permeability. Morphological studies have documented a close anatiomical association between mast cells and nonmyelinated nerves, that contain substance P and other neuropeptides. However, the presence of mast cells within nerve fasicles has not been previously examined ultrastructurally. In this study, we examined ultrastructurally the distribution of mast cells in the nerve fiber bundles located in the muscular connective tissue of rat tongues (n=20).

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